Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children

Abstract

Hepcidin is the master regulatory hormone that governs iron homeostasis and has a role in innate immunity. Although hepcidin has been studied extensively in model systems, there is less information on hepcidin regulation in global health contexts where iron deficiency (ID), anemia, and high infectious burdens (including malaria) all coexist but fluctuate over time. We evaluated iron status, hepcidin levels, and determinants of hepcidin in 2 populations of rural children aged ≤8 years, in the Gambia and Kenya (total n = 848), at the start and end of a malaria season. Regression analyses and structural equation modeling demonstrated, for both populations, similar combinatorial effects of upregulating stimuli (iron stores and to a lesser extent inflammation) and downregulating stimuli (erythropoietic drive) on hepcidin levels. However, malaria season was also a significant factor and was associated with an altered balance of these opposing factors. Consistent with these changes, hepcidin levels were reduced whereas the prevalence of ID was increased at the end of the malaria season. More prevalent ID and lower hepcidin likely reflect an enhanced requirement for iron and an ability to efficiently absorb it at the end of the malaria season. These results, therefore, have implications for ID and malaria control programs.

Figure 1

Study design and hepcidin and iron status at the start and end of the malaria season. (A) Study design at the Gambian site. (B) Study design at the Kenyan site. (C) Plasma hepcidin levels at the start and end of the season. (D) Proportion of iron-deficient children at the start and end of the season. (E) Ferritin levels at the start and end of the season. (F) Soluble transferrin receptor (sTfR) levels at the start and end of the season. CBC indicates complete blood count. Geometric means are presented for continuous variables. The same individual study participants contributed data at the start and end of the season. All analyses were adjusted for age.

Figure 2

Log-hepcidin correlates with log-ferritin and log-sTfR levels at the start and end of the malaria season. (A) Correlation between log-hepcidin and log-ferritin levels in Kenyan children. (B) Correlation between log-hepcidin and log-ferritin levels in Gambian children. (C) Correlation between log-hepcidin and log-sTfR levels in Kenyan children. (D) Correlation between log-hepcidin and log-sTfR levels in Gambian children. Red filled circles indicate values at the end of the malaria season; black unfilled circles, values at the start of the malaria season. The red line is the line of best fit at the end of the malaria season, and the black line is the line of best fit at the start of the malaria season. Pearson’s correlation coefficients and significance values are presented.

Figure 3

SEM of variables associated with hepcidin. A single SEM was created, grouped by site. The sizes of the associations are indicated by the standardized regression coefficients. *P < .005. A positive association is indicated by a black line, an inverse association by a red line, and a nonsignificant association by a dotted line. In Gambian children, age was additionally associated with log-ferritin levels (β 0.24; P < .0005), log-sTfR (β −0.17; P < .0005), and Hb levels (β 0.25; P < .0005); data not shown for simplicity. The R² was 0.49 for the Gambian group and 0.58 for the Kenyan group. The standard error (ε) was 0.02 for the Gambian group and 0.02 for the Kenyan group. The overall CFI was 1.0, and the RMSEA was <0.005 indicating a good fit.